Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Antimicrob Agents Chemother. 2011 Nov;55(11):5325-30. doi: 10.1128/AAC.00453-11. Epub 2011 Aug 22.
Cationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungus Pseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) the in vivo pharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) the in vivo efficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P < 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. These in vivo efficacies were equivalent and significantly correlated with three PK indices investigated: fC(max)/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC), fAUC/MIC (where AUC is the area under the concentration-time curve), and f%T(>MIC) (%T(>MIC) is the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (E(max)) model (R(2) > 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.
阳离子抗菌肽 (CAPs) 在宿主免疫防御中发挥重要作用。Plectasin 是一种从腐生真菌 Pseudoplectania nigrella 中分离出来的防御素样 CAP。NZ2114 是 plectasin 的一种新型变体，对革兰氏阳性菌具有强大的活性。在这项研究中，我们研究了 (i) NZ2114 的体内药代动力学和药效学 (PK/PD) 特征，以及 (ii) NZ2114 与两种常规抗生素万古霉素或达托霉素在实验性兔感染性心内膜炎 (IE) 模型中的体内疗效比较，该模型是由耐甲氧西林金黄色葡萄球菌 (MRSA) 菌株 (ATCC 33591) 引起的。所有 NZ2114 方案（5、10 和 20 mg/kg 体重，静脉内 [i.v.]，每天两次，共 3 天）均显著降低了心脏赘生物、肾脏和脾脏中的 MRSA 密度，与未治疗的对照组相比，除了一种情况（5 mg/kg，脾脏中的 MRSA 计数）。在所有目标组织中，NZ2114 的疗效明显呈剂量依赖性。在 20 mg/kg 时，NZ2114 的疗效明显优于万古霉素（P < 0.001），与达托霉素的疗效相似。重要的是，只有 NZ2114（10-和 20-mg/kg 方案）可防止心脏赘生物、肾脏和脾脏中的治疗后复发，而万古霉素和达托霉素治疗的动物的这些靶组织中的细菌计数继续增加。这些体内疗效等效，与三个研究的 PK 指标明显相关：fC(max)/MIC（血清中游离、未结合药物部分的最大浓度除以 MIC）、fAUC/MIC（其中 AUC 是浓度-时间曲线下的面积）和 f%T(>MIC)（%T(>MIC) 是药物浓度在稳态药代动力学条件下超过 MIC 的 24 小时内的累积百分比），通过 sigmoid 最大效应 (E(max)) 模型（R(2) > 0.69）进行分析。在这种 MRSA IE 模型中，NZ2114 的优越疗效表明该化合物有潜力进一步开发用于治疗严重的 MRSA 感染。
